1. Field of the Invention
The present invention relates to novel methods for the treatment of cancer. More specifically, the present invention relates to the inhibition of the hedgehog signaling pathway by the direct binding of a cyclopamine derivative to protein smoothened and uses thereof.
2. Description of the Related Art
The hedgehog (Hh) gene was identified by two Nobel laureates through genetic analysis of segmentation of fruit fly Drosophila (1). The seven transmembrane domain containing protein smoothened (SMO) serves as the key player for signal transduction of this pathway, whose function is inhibited by another transmembrane protein Patched (PTC) in the absence of hedgehog ligands. In the presence of active hedgehog ligands, binding of hedgehog to its receptor PTC releases this inhibition, allowing SMO to signal downstream, eventually to Gli transcription factors. As transcription factors, Gli molecules can regulate target gene expression by direct association with a specific consensus sequence located in the promoter region of the target genes (2,3).
The hedgehog signaling pathway is critical for stem cell functions and development of cancer. The major breakthrough in contemporary understanding of hedgehog signaling in human cancers came from the discovery that mutations of human homologue of the drosophila patched gene (PTCH1) are associated with a rare hereditary form of basal cell carcinoma (BCC)— Basal Cell Nevus Syndrome (also called Gorlin syndrome) (4-6). Recent studies indicate that Hh signaling is activated in many types of extracutaneous tumors, including brain tumors, gastrointestinal, prostate, lung and breast cancers (7). Specific signaling antagonists for the hedgehog pathway have been discovered and synthesized with significant clinical implications in novel cancer therapeutics. The successful phase I clinical trial with a hedgehog antagonist by Genentech further highlights the feasibility and clinical implications of inhibiting hedgehog signaling for cancer treatment.
Cyclopamine is shown to act through direct binding of smoothened (8). After the discoveries of connections between cyclopamine, the activity of hedgehog signaling pathway and cancer formation, scientists have directed efforts towards studies employing cyclopamine as the compound to inhibit the hedgehog pathway and offer potential cure for cancers. Several interesting findings have reported the effect of cyclopamine against various cancers (7). However, there are several issues associated with cyclopamine. Firstly, cyclopamine is not water-soluble which creates problems in drug delivery. Secondly, cyclopamine is toxic, causing off-target effects.
There is a need in the art for a cyclopamine derivative that is water-soluble, possesses low toxicity and is a potent inhibitor of the hedgehog pathway. The present invention fulfills this longstanding need in the art.